scholarly journals Structures of Pathological and Functional Amyloids and Prions, a Solid-State NMR Perspective

2021 ◽  
Vol 14 ◽  
Author(s):  
Asen Daskalov ◽  
Nadia El Mammeri ◽  
Alons Lends ◽  
Jayakrishna Shenoy ◽  
Gaelle Lamon ◽  
...  
Keyword(s):  
Solid State ◽  
Solid State Nmr ◽  
Protein Misfolding ◽  
Conformational Transition ◽  
Paramagnetic Resonance ◽  
Amyloid Aggregates ◽  
Functional Amyloids ◽  
Protein Deposition Diseases ◽  
Infectious Proteins ◽  
Amyloid Structures

Infectious proteins or prions are a remarkable class of pathogens, where pathogenicity and infectious state correspond to conformational transition of a protein fold. The conformational change translates into the formation by the protein of insoluble amyloid aggregates, associated in humans with various neurodegenerative disorders and systemic protein-deposition diseases. The prion principle, however, is not limited to pathogenicity. While pathological amyloids (and prions) emerge from protein misfolding, a class of functional amyloids has been defined, consisting of amyloid-forming domains under natural selection and with diverse biological roles. Although of great importance, prion amyloid structures remain challenging for conventional structural biology techniques. Solid-state nuclear magnetic resonance (SSNMR) has been preferentially used to investigate these insoluble, morphologically heterogeneous aggregates with poor crystallinity. SSNMR methods have yielded a wealth of knowledge regarding the fundamentals of prion biology and have helped to solve the structures of several prion and prion-like fibrils. Here, we will review pathological and functional amyloid structures and will discuss some of the obtained structural models. We will finish the review with a perspective on integrative approaches combining solid-state NMR, electron paramagnetic resonance and cryo-electron microscopy, which can complement and extend our toolkit to structurally explore various facets of prion biology.

scholarly journals Zinc-binding structure of a catalytic amyloid from solid-state NMR

2017 ◽  
Vol 114 (24) ◽  
pp. 6191-6196 ◽  
Author(s):  
Myungwoon Lee ◽  
Tuo Wang ◽  
Olga V. Makhlynets ◽  
Yibing Wu ◽  
Nicholas F. Polizzi ◽  
...  
Keyword(s):  
Solid State ◽  
Solid State Nmr ◽  
Protein Misfolding ◽  
Molecular Size ◽  
Advanced Materials ◽  
Side Chains ◽  
Evolution Of Life ◽  
Water Activation ◽  
Catalytic Reactivity ◽  
Molecular Bases

Throughout biology, amyloids are key structures in both functional proteins and the end product of pathologic protein misfolding. Amyloids might also represent an early precursor in the evolution of life because of their small molecular size and their ability to self-purify and catalyze chemical reactions. They also provide attractive backbones for advanced materials. When β-strands of an amyloid are arranged parallel and in register, side chains from the same position of each chain align, facilitating metal chelation when the residues are good ligands such as histidine. High-resolution structures of metalloamyloids are needed to understand the molecular bases of metal–amyloid interactions. Here we combine solid-state NMR and structural bioinformatics to determine the structure of a zinc-bound metalloamyloid that catalyzes ester hydrolysis. The peptide forms amphiphilic parallel β-sheets that assemble into stacked bilayers with alternating hydrophobic and polar interfaces. The hydrophobic interface is stabilized by apolar side chains from adjacent sheets, whereas the hydrated polar interface houses the Zn2+-binding histidines with binding geometries unusual in proteins. Each Zn2+ has two bis-coordinated histidine ligands, which bridge adjacent strands to form an infinite metal–ligand chain along the fibril axis. A third histidine completes the protein ligand environment, leaving a free site on the Zn2+ for water activation. This structure defines a class of materials, which we call metal–peptide frameworks. The structure reveals a delicate interplay through which metal ions stabilize the amyloid structure, which in turn shapes the ligand geometry and catalytic reactivity of Zn2+.

scholarly journals Huntingtin exon 1 fibrils feature an interdigitated β-hairpin–based polyglutamine core

2016 ◽  
Vol 113 (6) ◽  
pp. 1546-1551 ◽  
Author(s):  
Cody L. Hoop ◽  
Hsiang-Kai Lin ◽  
Karunakar Kar ◽  
Gábor Magyarfalvi ◽  
Jonathan M. Lamley ◽  
...  
Keyword(s):  
Solid State ◽  
Solid State Nmr ◽  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Chemical Shifts ◽  
Magic Angle Spinning ◽  
Cag Repeat ◽  
Magic Angle ◽  
Polyglutamine Expansion ◽  
Angle Spinning

Polyglutamine expansion within the exon1 of huntingtin leads to protein misfolding, aggregation, and cytotoxicity in Huntington’s disease. This incurable neurodegenerative disease is the most prevalent member of a family of CAG repeat expansion disorders. Although mature exon1 fibrils are viable candidates for the toxic species, their molecular structure and how they form have remained poorly understood. Using advanced magic angle spinning solid-state NMR, we directly probe the structure of the rigid core that is at the heart of huntingtin exon1 fibrils and other polyglutamine aggregates, via measurements of long-range intramolecular and intermolecular contacts, backbone and side-chain torsion angles, relaxation measurements, and calculations of chemical shifts. These experiments reveal the presence of β-hairpin–containing β-sheets that are connected through interdigitating extended side chains. Despite dramatic differences in aggregation behavior, huntingtin exon1 fibrils and other polyglutamine-based aggregates contain identical β-strand–based cores. Prior structural models, derived from X-ray fiber diffraction and computational analyses, are shown to be inconsistent with the solid-state NMR results. Internally, the polyglutamine amyloid fibrils are coassembled from differently structured monomers, which we describe as a type of “intrinsic” polymorphism. A stochastic polyglutamine-specific aggregation mechanism is introduced to explain this phenomenon. We show that the aggregation of mutant huntingtin exon1 proceeds via an intramolecular collapse of the expanded polyglutamine domain and discuss the implications of this observation for our understanding of its misfolding and aggregation mechanisms.

Anionic redox reactions and structural degradation in a cation-disordered rock-salt Li1.2Ti0.4Mn0.4O2 cathode material revealed by solid-state NMR and EPR

2020 ◽  
Vol 8 (32) ◽  
pp. 16515-16526 ◽  
Author(s):  
Fushan Geng ◽  
Bei Hu ◽  
Chao Li ◽  
Chong Zhao ◽  
Olivier Lafon ◽  
...  
Keyword(s):  
Electron Paramagnetic Resonance ◽  
Solid State ◽  
Rock Salt ◽  
Epr Spectroscopy ◽  
Solid State Nmr ◽  
Redox Reactions ◽  
Degradation Mechanism ◽  
Structural Degradation ◽  
Paramagnetic Resonance ◽  
Electron Paramagnetic

The cation-disordered rock-salt Li1.2Ti0.4Mn0.4O2 is studied by solid-state NMR and electron paramagnetic resonance (EPR) spectroscopy during the first cycle. The anionic redox and structural degradation mechanism are discussed.

Molecular structure of amyloid fibrils: insights from solid-state NMR

2006 ◽  
Vol 39 (1) ◽  
pp. 1-55 ◽  
Author(s):  
Robert Tycko
Keyword(s):  
Molecular Structure ◽  
Solid State ◽  
Solid State Nmr ◽  
Amyloid Fibrils ◽  
Structural Information ◽  
Amyloid Peptide ◽  
Magic Angle ◽  
Nmr Data ◽  
Β Amyloid ◽  
Amyloid Structures

1. Introduction 22. Sources of structural information in solid-state NMR data 52.1 General remarks 52.2 Chemical shifts, linewidths, and magic-angle spinning 62.3 Dipole–dipole couplings and dipolar recoupling 82.4 Tensor correlation techniques 122.5 Solid-state NMR of aligned samples 142.6 Indirect sources of structural information 152.7 Sample preparation for solid-state NMR 153. Levels of structure in amyloid fibrils 184. Molecular structure of β-amyloid fibrils 254.1 Self-propagating, molecular-level polymorphism in Aβ1–40 fibrils 254.2 Structural model for Aβ1-40 fibrils 284.3 Staggering of β-strands in Aβ1-40 fibrils 324.4 Structure of Aβ1-42 fibrils 344.5 Structure of fibrils formed by short β-amyloid fragments 344.6 Structures of non-fibrillar aggregates 355. Molecular structure of other amyloid fibrils 365.1 Ure2p10–39 and full-length Ure2p fibrils 365.2 TTR105–115 fibrils 385.3 HET-s fibrils 385.4 Amylin fibrils 395.5 PrP fibrils 395.6 ccβ fibrils 405.7 α-synuclein fibrils 405.8 Calcitonin fibrils 416. Data relevant to various proposals regarding amyloid structure 416.1 β-helical models for amyloid fibrils 416.2 Amyloid fibrils as water-filled nanotubes 426.3 Domain swapping in amyloid fibrils 426.4 The parallel superpleated β-structure model 436.5 α-sheet structures in amyloid fibrils 437. Conclusions 448. Acknowledgments 469. References 46Solid-state nuclear magnetic resonance (NMR) measurements have made major contributions to our understanding of the molecular structures of amyloid fibrils, including fibrils formed by the β-amyloid peptide associated with Alzheimer's disease, by proteins associated with fungal prions, and by a variety of other polypeptides. Because solid-state NMR techniques can be used to determine interatomic distances (both intramolecular and intermolecular), place constraints on backbone and side-chain torsion angles, and identify tertiary and quaternary contacts, full molecular models for amyloid fibrils can be developed from solid-state NMR data, especially when supplemented by lower-resolution structural constraints from electron microscopy and other sources. In addition, solid-state NMR data can be used as experimental tests of various proposals and hypotheses regarding the mechanisms of amyloid formation, the nature of intermediate structures, and the common structural features within amyloid fibrils. This review introduces the basic experimental and conceptual principles behind solid-state NMR methods that are applicable to amyloid fibrils, reviews the information about amyloid structures that has been obtained to date with these methods, and discusses how solid-state NMR data provide insights into the molecular interactions that stabilize amyloid structures, the generic propensity of polypeptide chains to form amyloid fibrils, and a number of related issues that are of current interest in the amyloid field.

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